Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice

Sandra K. Erickson, Steven R. Lear, Sean Deane, Sandrine Dubrac, Sandra L. Huling, Lien Nguyen, Jaya S. Bollineni, Sarah Shefer, Hideyuki Hyogo, David E. Cohen, Benjamin Shneider, Ephraim Sehayek, Meena Ananthanarayanan, Natarajan Balasubramaniyan, Fredrick J. Suchy, Ashok K. Batta, Gerald Salen

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Cholesterol 7α-hydroxylase, a rate-limiting enzyme for bile acid synthesis, has been implicated in genetic susceptibility to atherosclerosis. The gene, CYP7A1, encoding a protein with this activity, is expressed normally only in hepatocytes and is highly regulated. Our cyp7A1 gene knockout mouse colony, as young adults on a chow diet, is hypercholesterolemic. These mice were characterized extensively to understand how cyp7A1 affects lipid and bile acid homeostasis in different tissue compartments and whether gender plays a modifying role. Both male and female cyp7A1-deficient mice had decreased hepatic LDL receptors, unchanged hepatic cholesterol synthesis, increased intestinal cholesterol synthesis and bile acid transporters, and decreased fecal bile acids but increased fecal sterols. In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile. Taken together, the data suggest that cyp7A1 deficiency results in a proatherogenic phenotype in both genders and leads to a prolithogenic phenotype in females.

Original languageEnglish (US)
Pages (from-to)1001-1009
Number of pages9
JournalJournal of Lipid Research
Volume44
Issue number5
DOIs
StatePublished - May 2003

Keywords

  • Bile acid transporters
  • Fatty acids
  • Intestine
  • Lipid synthesis
  • Liver
  • Low density lipoprotein receptors
  • Sterol 27-hydroxylase

ASJC Scopus subject areas

  • Endocrinology

Fingerprint Dive into the research topics of 'Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice'. Together they form a unique fingerprint.

  • Cite this

    Erickson, S. K., Lear, S. R., Deane, S., Dubrac, S., Huling, S. L., Nguyen, L., Bollineni, J. S., Shefer, S., Hyogo, H., Cohen, D. E., Shneider, B., Sehayek, E., Ananthanarayanan, M., Balasubramaniyan, N., Suchy, F. J., Batta, A. K., & Salen, G. (2003). Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice. Journal of Lipid Research, 44(5), 1001-1009. https://doi.org/10.1194/jlr.M200489-JLR200